Periodontal disease, with caries, is the most important cause of loss of teeth. It is well established that bacteria are directly involved in both the onset and progression of periodontal disease. See for example J. Slots, "Subgingival Microflora and Periodontal Disease," J. Clin. Periodontal. 6, 315 (1979) and S. S. Socransky, "Microbiology of Periodontal Disease--Present Status and Future Considerations," J. Periodontol. 48, 497 (1977). This has led to the widespread use of antibiotics in the treatment of periodontal disease, and particularly to the use of tetracycline, since significantly higher levels of tetracycline are found in gingival fluid than in blood after administration of single or multiple oral doses. (J. M. Gordon et al., "Sensitive Assay for Measuring Tetracycline Levels in Gingival Crevice Fluid," Antimicrob. Agents Chemother. 17, 193 (1980), J. M. Gordon et al., "Concentrations of Tetracycline in Human Gingival Fluid after Single Doses," J. Clin. Peridontol. 8, 117 (1981) and J. M. Gordon et al., "Tetracycline: Levels Achievable in Gingival Crevice Fluid and in vitro Effect on Subgingival Organisms. Part 1. Concentrations in Crevicular Fluid after Repeated Doses," J. Periodontol. 52, 609 (1981).) However, the typical effective tetracycline oral dose of one gram per day for 30 days can lead to serious side effects. It has been estimated that the dose should be of the order of one hundred times smaller to avoid these effects. A more satisfactory approach then is to administer the antibiotic topically using a controlled release device to sustain an effective dose for the required length of time. Because the drug is delivered locally, a much reduced dose will suffice for effective therapy, and harmful side effects can be reduced or eliminated.
Long lasting drug delivery systems presently used in the oral cavity fall broadly into two groups; either troches, pastilles or tablets which adhere to the oral mucosa in some way, or drug containing strips or dosage forms which are attached to the gums, teeth or other interior surface of the mouth. A good example of the former category is U.S. Pat. No. 4,039,653. This patent discloses a sustained release tablet coated with a pharmaceutically acceptable oral adhesive, which is placed in an upper corner of the mouth and is capable of dispensing an odor-masking agent, local anaesthetic or other medication in a sustained fashion for periods of up to twelve hours. U.S. Pat. No. 4,250,163 discloses a method of administering a broad range of medications to the oral cavity by means of a water-swellable and mucosa-adhesive polymeric matrix, which can be in the form of a tablet, powder or granules and which is effective for times of the order of a few hours. As can be seen from these and other examples, such as U.S. Pat. Nos. 4,226,848, 4,369,172 and 4,059,686, such troches and tablets are normally effective for periods of hours rather than days, and a course of treatment lasting one month would require the use of numerous tablets. Furthermore they are inappropriate to the treatment of periodontal disease because the drug is released into the saliva or oral mucosa, and does not penetrate the periodontal pocket to any significant extent. Buccal tapes, strips and forms suffer from the same disadvantages. For example, the buccal dosage form disclosed in U.S. Pat. No. 3,972,995 was found to be effective without leaking, if not wrinkled or dislodged by the teeth, for about one hour only. This highlights another disadvantage of existing methods of dispensing drugs for oral therapy; they may slip or be dislodged by the tongue or teeth, may be uncomfortable to a greater or lesser degree, and may interfere with the normal oral functions to some extent. Recent developments in the art are directed toward delivering the therapeutic agent directly to the periodontal pocket, in some cases in a controlled release formulation. Gordon et al. have described the use of a drug-filled polymer hollow fiber. (J. M. Goodson et al., "Periodontal Therapy by Local Delivery of Tetracycline," J. Clin. Periodontol. 6, 83 (1979), J. Lindhe et al., "Local Tetracycline Delivery Using Hollow Fiber Devices in Periodontal Therapy," J. Clin. Periodontol. 6, 141 (1979) and R. L. Dunn et al.,"Monolithic Fibers for Controlled Delivery of Tetracycline," in Proc. Ninth Int. Symposium on Controlled Release of Bioactive Materials, Ft. Lauderdale, Fl., July (1982).) This device is tied around a tooth and gently pressed below the margin of the gingiva so that it resides in the periodontal pocket, and is capable of delivering an effective dose of 2.5 micrograms of tetracycline per day per periodontal pocket for a prolonged period of a week or more. Similar results have been obtained by Coventry and Newman (J. Coventry and H. N. Newman, "Experimental Use of a Slow Release Device employing Chlorhexidine Gluconate in Areas of Acute Periodontal Inflammation," J. Clin. Periodontol. 9, 129 (1982)) and Addy et al. (M. Addy et al., "The Development and in vitro Evaluation of Acrylic Strips and Dialysis Tubing for Local Drug Delivery," J. Periodontol. 53, 693 (1982)) using acrylic strips 1 mm or more long, impregnated with chlorhexidine, tetracycline or metronidazole, which were inserted into the periodontal pocket with tweezers. Such a strip, formed from ethylcellulose impregnated with metronidazole, is disclosed by Loesche in U.S. Pat. No. 4,568,538. Another strip, employing a water soluble polymer of a particular elasticity and viscosity, is disclosed by Suzuki et al. in U.S. Pat. No. 4,569,837. Although these devices may be able to dispense an appropriate drug for a time span of a week or more, they are inappropriate to widespread use because they are difficult and time consuming to apply and may be dislodged by the patient during normal oral functions.
U.S. patent application Ser. No. 856,961, copending with the present invention, provides a novel controlled release system that can deliver antibiotics or other drugs in the periodontal pocket for a prolonged period of time, without interfering in any way with normal oral functions.
The present invention provides for the controlled delivery of a range of agents that are efficacious in the treatment of periodontal disease and other gingival or oral problems.